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Abstract

Background

Cyclic vomiting syndrome (CVS), defined by recurrent stereotypical episodes of nausea
and vomiting, is a relatively-common disabling and historically difficult-to-treat
condition associated with migraine headache and mitochondrial dysfunction. Limited
data suggests that the anti-migraine therapies amitriptyline and cyproheptadine, and
the mitochondrial-targeted cofactors co-enzyme Q10 and L-carnitine, have efficacy
in episode prophylaxis.

Methods

A retrospective chart review of 42 patients seen by one clinician that met established
CVS diagnostic criteria revealed 30 cases with available outcome data. Participants
were treated on a loose protocol consisting of fasting avoidance, co-enzyme Q10 and
L-carnitine, with the addition of amitriptyline (or cyproheptadine in those < 5 years)
in refractory cases. Blood level monitoring of the therapeutic agents featured prominently
in management.

Results

Vomiting episodes resolved in 23 cases, and improved by > 75% and > 50% in three and
one additional case respectively. Among the three treatment failures, two could not
tolerate amitriptyline (as was also the case in the child with only > 50% efficacy)
and one had multiple congenital gastrointestinal anomalies. Excluding the latter case,
substantial efficacy (> 75% response) was 26/29 at the start of treatment, and 26/26
in those able to tolerate the regiment, including high dosages of amitriptyline.

Background

Cyclic vomiting syndrome (CVS) is characterized by recurrent identical episodes of
nausea and vomiting, with the absence of these symptoms between episodes [1]. CVS is likely common, being present in about 2% of Scottish [2] and Western Australian [3] school children. Prior to the advent of successful therapy, CVS was a disabling condition
as episodes are generally severe, usually last for days, and often require intravenous
fluid therapy for dehydration [1]. Frequent and prolonged school or work absences lead to academic or work disability.
CVS can pose a challenge for clinicians to manage, and it is common for patients to
seek help from multiple practitioners because of continued vomiting episodes.

Although the etiology is unknown, substantial parallels with migraine headache [4] have prompted therapeutic trials with anti-migraine therapies. Amitriptyline (Elavil®), a tricyclic "antidepressant" frequently used to treat migraine, is the most widely
prescribed prophylactic medication used for the treatment of CVS, with response rates
varying from 52-73% in open-label and subject recall-based studies in children and
adults [reviewed in 5]. In a recent consensus statement, amitriptyline was recommended
as the first-line treatment choice for CVS prophylaxis in children and adolescents
age 5 years and older, while cyproheptadine is recommended in younger children [1].

Mitochondrial dysfunction is hypothesized to be a factor in the pathogenesis of both
CVS and migraine headache based upon decreased respiratory complex enzymology, disease-associated
mitochondrial DNA (mtDNA) sequence variants, and preferential maternal inheritance
[reviewed in 5]. Physicians and other health care providers are increasingly recommending
co-enzyme Q10, also known as ubiquinone, a commonly-used dietary supplement that is
widely available in retail settings, for the treatment of a wide variety of conditions,
including mitochondrial dysfunction. Co-enzyme Q10 serves as the electron shuttle
between complexes 1 or 2 and complex 3 of the mitochondrial respiratory chain [6]. In migraine, a randomized control trial demonstrated therapeutic efficacy [7]. Recently, the use of co-enzyme Q10 has been gaining in popularity among CVS patient
groups. A recent subject recall-based study in CVS suggested equivalent efficacy of
co-enzyme Q10 and amitriptyline (~70%), but with superior tolerability of co-enzyme
Q10 [5]. There was inadequate data to assess response to combination therapy with both agents.

L-carnitine is also a naturally-occurring dietary supplement that is frequently used
in the treatment of mitochondrial dysfunction [6]. L-carnitine is a shuttle of long-chain fatty acids across the inner mitochondrial
membrane and thus is required for fat oxidation. In addition, L-carnitine has a "detoxifying"
role in shuttling accumulated intermediates of metabolism out of impaired mitochondria.
One case series [8] demonstrated efficacy of L-carnitine in CVS prophylaxis.

In the author's clinical experience, episodes of nausea and vomiting diminish markedly
in the vast majority of CVS patients treated with a protocol consisting of fasting
avoidance, co-enzyme Q10, and L-carnitine, with the addition of amitriptyline or cyproheptidine
in refractory participants over and under the age of five years, respectively. One
essential aspect of this protocol is dosing based on blood levels. The current study
is a retrospective chart review of the 42 CVS patients evaluated over a two-year period
by the author to evaluate therapeutic responses.

Methods

A computer-generated report of all clinic patients seen by the author during the two-year
period from 7/1/06 to 6/30/08 was reviewed for ICD 9 codes used by the author for
CVS patients, including 536.2 and 277.87. A medical record review was performed on
all cases so identified. Patients were included as participants in this study if given
a diagnosis of CVS by the author based on fulfilling both the NASPGHAN [1] and Rome III [9] criteria. All participants are unrelated. All records were reviewed up until 6/30/10,
allowing for a two-year follow-up period to access medium-term treatment responses.
This study was approved by the Children's Hospital Los Angeles Institutional Review
Board.

Participants were treated on a clinical basis, and not as part of a prospective study;
however, treatment during this period was standardized as based on prior clinical
experience and the literature [1]:

• Dietary: All subjects were advised to make dietary changes [1], including the "3+3 diet" (3 meals and 3 snacks a day including between meals and
at bedtime), and the avoidance of fasting.

• Co-enzyme Q10: Participants were treated with co-enzyme Q10 (ubiquinone) in liquid
or gel capsule form (from a variety of brands) at a starting dose of 10 mg/kg/day,
or 200 mg, divided twice a day, whichever is smaller.

• L-carnitine: Participants were treated with Carnitor brand or generics at a starting
dose of 100 mg/kg/day divided BID, or 2 grams twice a day, whichever is smaller. A
small minority of families, all with untreated free carnitine blood levels > 30 micromolar,
were not treated.

• Amitriptyline: Participants age 5 years and over with continued vomiting episodes
despite the above therapies were treated at a starting dose of 0.5 mg/kg/day given
at night An EKG was performed looking at the QTc interval prior to and a few weeks
following starting treatment.

• Cyproheptadine: Participants under the age of 5 years with continued vomiting episodes
despite the above therapies were treated at a starting dose of 0.25 mg/kg/day divided
twice a day.

• Topiramate: Two participants who were refractory to all of the above measures were
started on 25 mg of topiramate twice a day.

Dosages were increased every one to a few months until one of the following occurred:

• Resolution of vomiting episodes

• Intolerable side effects that failed a reduction in dosage followed by a slow dosage
increase

*Blood levels were not routinely monitored for dosages < 1 mg/kg/day as they were
uniformly low in the authors' prior experience.

Efficacy was queried in terms of two parameters: episode frequency and episode duration.
The efficacy category was determined by the percent improvement in the parameter demonstrating
the greatest response at the time of the most-recent clinic visit prior to 6-30-10:

• Resolution (episodes resolved, allowing for one episode a year with an obvious trigger,
usually a febrile infection).

Results

A total of 42 participants met the study criteria. Age at the time of chart review
varied from 3 to 26 years, with a median of 12 years. The age of the onset of vomiting
episodes was 1 week to 15 years, with a median of 4 years. The female:male ratio was
2.2:1 (29 females and 13 males). The race/ethnicity was 28 (67%) Caucasians, 11 (26%)
Hispanics, 2 (5%) African-Americans, and 1 (2%) Native-American. Several co-morbid,
predominantly-"functional", conditions were common, ranging from zero (in two adults)
to 16 per participant, with a median of 5.5 co-morbid conditions (Table 1).

Table 1. Chronic co-morbidities at 10% or greater prevalence among the 42 participants

The inheritance pattern as estimated by Quantitative Pedigree Analysis [10] in the 35 cases with available data was 21 (60%) participants with probable maternal
inheritance, 4 (11%) indeterminate, and 10 (29%) with probable non-maternal inheritance.

Nine participants were excluded from outcome analyses because they were seen in clinic
only once or twice, and no follow-up data was available to determine their response
to therapy, including five of the 10 adults (age > 18 years), but only 4 of the 32
children (P = 0.02). Two additional children were excluded because CVS resolved prior to starting
therapy. One additional case was excluded because the parents declined prophylactic
therapy and chose to continue to abort episodes with lorazepam and diphenhydramine.

Records in the remaining 30 subjects were queried for data related to treatment response
(Table 2). This included three participants over the age of 18 years who were included in
the study as they are of ages commonly treated by pediatricians, and the physiology
of youth in their early to mid 20s is similar to that of adolescents.

The treatment protocol failed in three cases, and was sub-optimal (50-75% response)
in another case. In one of the treatment failure cases, episodes completely resolved
for several months on amitriptyline alone. Unfortunately, a prolonged QTc interval
was noted, which resolved on discontinuation without adverse events. Episodes then
returned, but further therapy and evaluation were complicated by severe non-compliance.
Two participants on amitriptyline, co-enzyme Q10, and carnitine had tolerance issues
with amitriptyline. One of them (also labeled as treatment failure) demonstrated good
efficacy, yet amitriptyline was discontinued because of narcolepsy, and episodes returned.
In the other case (labeled as sub-optimal), behavioral and emotional effects have
limited treatment to a sub-therapeutic amitriptyline level associated with only partial
efficacy. In the final case of treatment failure, no improvement was noted on the
same three treatments, as well as with the further addition of cyproheptadine. This
latter infant has multiple malformations, including esophageal atresia, tracheoesophageal
fistula, imperforate anus, and a tethered spinal cord, as part of VATER association,
and thus was excluded from further data analyses.

Six participants reported side effects with amitriptyline. In addition to the three
cases discussed above in which side effects necessitated treatment discontinuation
or reduction, in three other participants side effects (increased frustration in two,
one also with insomnia, dizziness in the other) did not limit treatment. One participant
discontinued co-enzyme Q10 because of a pseudoporphyria rash. Such an association
has not been reported, and the rash did not reappear on treatment with another brand
of co-enzyme Q10. Cyproheptadine caused lethargy in one participant, and two had vague
non-specific sensations while on multiple medications both related and unrelated to
this study.

Urine ketosis was noted in the medical record as positive in 20 out of 20 cases tested
during vomiting episodes. Ketosis was not seen at baseline.

Discussion

This case series demonstrates excellent efficacy of cofactor therapy (co-enzyme Q10,
L-carnitine) combined with amitriptyline. Treatment responses were suboptimal in only
four cases, three of which could not tolerate adequate dosages of amitriptyline, and
never achieved a "therapeutic" blood level (> 80 ng/ml of amitriptyline + nortriptyline).
With the removal of the fourth case of the infant with multiple gastrointestinal malformations,
substantial efficacy (> 75% response) of this protocol in children and youth > age
5 years was 19/22 at the onset of treatment, and 19/19 in participants able to tolerate
amitriptyline. In the author's observations, making treatment decisions contingent
of the blood levels of co-enzyme Q10, carnitine and amitriptyline was very helpful
in many cases, as children with sub-optimal clinical improvement always demonstrated
a low level of at least one of the three agents, and increased dosing was associated
with the resolution of episodes. In order to achieve these "therapeutic" blood levels
and clinical efficacy, some subjects required higher-than-customary dosages, including
up to 25 mg/kg/day (800 mg a day in larger subjects) of co-enzyme Q10 and 2 mg/kg/day
of amitripyline. These dosages were well tolerated.

In participants under age five years, efficacy appears to be good when cofactor therapy
is combined with cyproheptadine, although the number of cases reported here is small.
Drug treatment varied by age in the present study and in the NASPGHAN recommendations
due to expert opinion regarding low tolerability (tachycardia and increased frustration)
of amitriptyline in younger children and low efficacy of cyproheptadine in older children
[1].

Combining the 22 cases > age 5 years and 4 cases < 5 years, overall substantial efficacy
(> 75% response) of this protocol was 23/26 at the start of treatment, and 23/23 of
those who could tolerate the regiment.

Clinical [11] and molecular [12] data suggest that CVS in adults, in particular with the adult onset of vomiting episodes
[12] is distinct in many ways than CVS in children. However, among the five adult cases
with outcome data in the present study, all of which had the adolescent onset of vomiting
episodes, two did not tolerate amitriptyline (see footnote 5 in Table 2) and in the three others episodes resolved (two with all three agents, one with amitriptyline
alone). Thus, there is inadequate data in this generally-young cohort to suggest alternative
management based on adult age, although there may be a higher rate of intolerance
to amitriptyline in adults than in children over age 5.

The major limitation on this study is that the participants were treated on the basis
of best available clinical therapy, not on a prospective clinical trial. The protocol
was used as guidelines, not on a rigorous basis. For example, participants with severe
disease (multiple hospitalizations) were often treated simultaneously with cofactors
and medication (amitriptyline or cyproheptadine) at the first visit based on the authors'
experience of frequent treatment failures on cofactors alone, while those with milder
disease courses were always given a trial of cofactors alone. Some families started
the therapies sequentially, and once episodes stopped or greatly diminished would
elect not to treat with agents not yet attempted. A few families declined co-enzyme
Q10 therapy due to costs, which unlike all the other therapies in this report was
rarely covered by insurance. A small number of participants were referred to the author
with partial efficacy on amitriptyline or cyproheptadine, and when episodes resolved
after increasing the dosage the families chose not to start one or both cofactors.
These factors contributed to the complexity of the medical regiments as listed in
Table 2. However this limitation does not diminish the observations herein of very-high efficacy
in general using these agents in clinical practice, either alone or in combination.

The participants in this study include cases diagnosed by the author in a primary
care-like setting, tertiary care cases referred by local pediatricians and gastroenterologists,
and quaternary care cases from other states that failed multiple previous attempts
at therapy. Since most participants were ascertained in the latter two situations,
the present cohort is a sicker, more-treatment-resistant population of CVS than is
likely to be encountered by all but a few practitioners. Since the more mildly-affected
participants often responded well to cofactor therapy alone, and that the side effects
of the cofactors are generally much less than that of the medications [5 and author's
experience], a trial of cofactor and dietary therapy alone may be warranted in most
CVS patients encountered in clinical practice, with amitripyline or cyproheptidine
added in refractory cases.

Many participants discontinued therapy at some point, and in most the episodes returned,
later resolving again on renewed therapy. In the exceptional cases, vomiting episodes
evolved into migraine headache, often at the time of puberty, and the same protocol
was used successfully in migraine prophylaxis. No participants are known to be off
therapy and without both vomiting episodes and migraine in the medium-term follow-up
period of this study.

Conclusions

CVS is a disabling, common and difficult-to-treat condition. Our data suggest that
a protocol consisting of mitochondrial-targeted cofactors (co-enzyme Q10 and L-carnitine)
plus amitriptyline (or possibly cyproheptadine in preschoolers) coupled with fasting
avoidance and blood level monitoring is highly effective in the prevention of vomiting
episodes. A prospective blinded clinical trial is needed. However, given the suggestion
of efficacy and excellent tolerability, health care providers may want to consider
combining these cofactors as a low-risk therapeutic option along with the NASPGHAN
recommendations of amitriptyline (> 5 years) or cyproheptadine (< 5 years). A trial
first of cofactors and fasting avoidance alone may be warranted in cases without a
history of multiple hospitalizations for vomiting episodes.

Competing interests

The author declares that they have no competing interests.

Authors' contributions

Not applicable, the sole author, RGB, performed all tasks.

Acknowledgements

Funding for logistical assistance such as publication costs was provided by the Cyclic
Vomiting Syndrome Association http://www.cvsaonline.org.